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Esophageal and Gastric Cancer
Peter C. Enzinger, MD
Director, Center for Esophageal and Gastric Cancer
Dana-Farber Cancer Institute
Associate Professor, Harvard Medical School
Disclosures:
• Consultant:
• Astellas
• Celgene
• Five Prime
• Lilly
• Loxo
• Merck
• Taiho
Cancer Site Incidence Deaths
Esophagus
Stomach
16,940
28,000
15,690
10,960
Esophagogastric Cancer 2017
USA
Males in USAFemales in USA
Incidence of Gastric Adenocarcinoma
CA Cancer J Clin ‘08
Brown. J. Natl. Cancer Inst. 2008
Trends in Esophagogastric Cancer:
++++ > 8-fold risk
+++ 4-8-fold risk
++ 2-4-fold risk
+ < 2-fold risk
+/- Conflicting studies
--- No proven risk
Risk Factor SCC ADC Tobacco +++ ++ ETOH +++ --- Barrett’s Esophagus --- ++++ Weekly Reflux Symptoms --- +++ Obesity --- ++ Poverty ++ --- Achalasia ++++ Caustic injury to esophagus ++++ --- Tylosis (NEPPK) ++++ --- Plummer-Vinson syndrome ++++ --- History of head & neck cancer ++++ --- H/o breast ca treated with radiotherapy +++ ++ Frequent consumption of hot beverages + --- HPV (China, Japan, South Africa) +/- --- Beta blocker --- +/- Anticholinergics --- +/- Aminophylines --- +/-
Risk Factors:
Esophageal CA
Enzinger & Mayer. N Engl J Med 2003
0
2
4
6
8
10
12
14
16
18
0 20-29 30-39 40 + 0 3.5 11 14.5 25 28.5 36+
Adenocarcinoma
Squamous Cell Carcinoma
Adenocarcinoma
Squamous Cell Carcinoma
Cigarettes per Day Drinks per Week
Data from Takezaki 2000, Wu 2001 and Brown 2001
Tobacco/Alcohol and Esophageal Cancer
1-19
Squamous
epitheliumMetaplasia
Low-
Grade
Dysplasia
High-
Grade
DysplasiaADC METS
Oxidative stress
Inflammation
G1&G2
COX-2
BCL-2
4%/yr
0.5%/yr
1%/yr
5%/yr10%
GERD1:7 Americans
0.005%/yr
Early Genetic Events:
17pLOH p53; 9pLOH p16
cyclin D1
2nd Tier Genetic Events:
p53 mutation; p16 mutation/methylation
EGF(R), telomerase RNA
Late Genetic Events:
4 N (G2) aneuploidy of 5q/13q
and LOH of 5q/13q(Rb)/18q
?
c-erbB2
E-cadherin-catenin
85+%
Neoplastic Progression of Barrett’s Esophagus
Risk Factors
for
Gastric
Adenocarcinoma
• Nutritional
– Low fat or protein consumption
– Salted meat or fish
– High nitrate consumption
• Environmental
– Poor food preparation (smoked)
– Lack of refrigeration
– Poor drinking water (well water)
– Occupation (rubber, coal workers)
– Smoking (1.6x)
– Low social class
• Medical
– Prior gastric surgery
– Helicobacter pylori infection (2x)
– Gastric atrophy and gastritis
Helicobacter pylori
N=0
mutagens
Higher pH
Bacterial growth + nitrate
Gastric
ascorbic acid
B-carotene
Proposed Cascade of
Pathologic Events in
Gastric Adenocarcinoma
Salt
Normal Superficial
gastritis
Atrophic
gastritisMetaplasia Dysplasia Carcinoma
Salt N-nitroso Chronic inflammation
carcinogens and reactive oxygen species
inhibition
promotion
Adapted from Correa
Hereditary Gastric Cancer• 1-3% of all gastric cancers:
• Hereditary Diffuse Gastric Cancer (HDGC):
– E-cadherin/CDH1 Germline Mutation
– Autosomal dominant
• families with > 2 patients with gastric cancer at any age, one confirmed DGC
• individuals with DGC before the age of 40
• families with diagnoses of both DGC and LBC (one diagnosis < age 50)
– 70% risk of DGC; 40% risk of lobular breast cancer (LBC)
– Prophylactic total gastrectomy
• Li-Fraumeni syndrome Lynch syndrome
• Peutz-Jeghers syndrome Hereditary breast and ovarian cancer
• Familial adenomatous polyposis Juvenile polyposis syndrome
• MUTYH-associated adenomatous polyposis (MAP)
• PTEN hamartoma tumor syndrome (Cowden syndrome)
Van der Post, RS. J Med Genet. 2015 Jun; 52(6): 361–374.
The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Genomic Characterization of Esophagogastric Cancer
CIN: chromosome instability
EBV: ebstein-barr virus
MSI: microsatellite instability
GS: genomically stable
Presented by: Peter C. Enzinger, MD
The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Genomic Characterization of Esophagogastric Cancer
The Cancer Genome Atlas Research Network. Nature . 2017; 1–9
Presented by: Peter C. Enzinger, MD
Mutations, copy #, & translocations across gastric molecular subtypes
The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Presented by: Peter C. Enzinger, MD
Localized Esophageal Cancer
What Can Surgery
Accomplish?
Localized Esophageal Cancer Treated With Surgery
Rice, Blackstone, Rusch. Ann Surg Oncol 2010
Localized Esophageal Cancer
Does (Neo)Adjuvant
Chemotherapy
Improve Surgical Outcomes?
Neoadjuvant Chemotherapy Compared with Surgery
Alone for Localized Esophageal Cancer
Sjoquist et al. Lancet Oncol 2011;12(7):681-92
Localized Esophageal Cancer
Does Neoadjuvant
Chemoradiation
Therapy Improve
Surgery Outcomes?
All-Cause Mortality Estimates for Neoadjuvant C/RT Compared with Surgery Alone
Sjoquist et al.
Lancet Oncol 2011;
12(7):681-92
CROSS Study: Schema
• Chemoradiotherapy regimen: • Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29• Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
• Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
Van Hagen et al. N Engl J Med 2012;366:2074-84.
CROSS Study: Overall survival
Van Hagen et al. N Engl J Med 2012;366:2074-84.
HR, 0.657; 95% CI 0.495-0.871
24.0 mo 49.4 mo
POET: Schema
Arm A
Week
Arm B
PLF I PLF III (3 weeks)
15 x 2 Gy in 3 weeks
PE (1 week)
Surgery
Surgery
1 1314 17 20-21
PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d1,8,15,22,29,36
PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5
PLF II
6 7
PLF I PLF II
Stahl M, et al. J Clin Oncol.2009;27:851-856.
POET: Overall Survival (Long-term Results)
Stahl M, et al. J Clin Oncol.2009;27:851-856.
Stahl M, et al. Eur J Cancer.2017;183-190.
Median Survival:
C→C→S C→C/RT→S
21.1 mo 30.8 mo
3yr 5yr
47% 40%
26% 24%
Can Surgery Improve
the Outcome of
Chemoradiation?
Localized Esophageal Cancer
Schema
tumor size
histology
weight loss
2 x Cisplatin (75 mg/m2)
+
5-fluorouracil (1000 mg/m2/d CI x 4d)
+
radiation therapy (5000 cGy)
R
A
N
D
O
M
I
Z
E
radiation therapy (6400 cGy)
Herskovic A, et al. N Engl J Med. 1992;326:1593-1598.
al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.
Prospective Randomized Intergroup Study:Radiation Therapy vs Chemotherapy + Radiation Therapy for Localized SCC or ADC of the Esophagus
Herskovic A, et al. N Engl J Med. 1992;326:1593-1598. al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.
Intergroup Study
Stratification :
• adenocarcinoma vs squamous cell vs adenosquamous
• pretreatment weight loss < 10% vs ≥ 10%
• performance status: 0 vs 1 vs 2
• center
Inoperable
esophageal
cancer
R
A
N
D
O
M
I
Z
E
50 Gy/5 weeks
+ Folfox, 3 cycles
50 Gy/5 weeks +
5FU/cisplatin, 2 cy.
Folfox, 3
cycles
5FU/cisplatin, 2
cycles
Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.
Prodige 5 - ACCORD 17 - Schema
FOLFOX: more gr. 1-2 PN, fewer toxic & sudden deaths, less mucositis, less alopecia,
decreased renal toxicity, shorter chemotherapy (12 days vs 16-20 days) in an outpatient
setting. Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.
Prodige 5 - ACCORD 17 - Survival
• A total of 455 patients with localized esophageal cancer were given 2 courses of 5-FU/cisplatin plus radiation therapy.
• 259/455 patients experienced a “partial response”, were considered operative candidates, and entered the randomized component of the trial.
Bedenne. J Clin Oncol. 2007;25:1160-1168.
Chemoradiation Therapy With or Without Surgery: French Phase III Trial
Survival
3-month mortality median 2-year
5-FU/CDDP x 3
+
1%
Radiation therapy
19.3
months
40%
P=0.56
Surgery 9% 17.7 months
34%
Partial Response
R
A
N
D
O
M
I
Z
E
(259 pts)
Bedenne. J Clin Oncol. 2007;25:1160-1168.
Chemoradiation Therapy With or Without Surgery: French Phase III Trial
Patients:
(N = 177)
uT3-4,N0-1, M0
with SCC
R
A
N
D
O
M
I
Z
E
3 cycles:
5-FU/LV +
Cisplatin +
Etoposide
Chemoradiation:
Cisplatin + Etoposide
+ 40 Gy RT
→ Surgery
Chemoradiation:
Cisplatin + Etoposide
+ > 60 Gy RT
Stahl. J Clin Oncol. 2005;23:2310-2317.
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Schema
Arm Completed
Treatment
Treatment
Mortality
3-yr Local
Recurrence
Median
Survival
3-Year Survival
Induction Chemo
All Responder
Arm A:
C/RT →S 62% 12.8% 41% 16 mo. 31% 54%
Arm B:
C/RT 85% 3.5%
(P = 0.03)
64%
(P = 0.004)
15 mo. 24%
(P = 0.02)
54%
Stahl. J Clin Oncol. 2005;23:2310-2317.
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Results
Stahl. J Clin Oncol. 2005;23:2310-2317.
Median survival (N = 172):
Arm A (C/RT →S) -16.4 months
Arm B (C/RT only)-14.9 months
31.3% (P = 0.02)
24.4%
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Survival
Localized Esophageal
Pre-operative cisplatin/5-FU chemotherapy offers a
small survival advantage in distal esophageal and GE
junction cancer.
Neoadjuvant platinum-based chemoradiation (esp. w.
carbo/tax) offers a greater survival advantage with
better local control but increased surgical morbidity.
Surgery may not be needed in patients who have a
clinical response to chemoradiation. FOLFOX may
be the best choice for these patients.
Conclusions from these Studies
What Can Surgery
Accomplish?
Localized Gastric Cancer
Survival for Resected Localized Gastric Cancer
Survival for 10,601 patients with resected gastric cancer
using SEER data 1973-2005 and AJCC 7th ed.Washington. Ann Surg Oncol 2010
What are Proven Strategies to
Enhance Outcomes for
Surgical Resection?
Localized Gastric Cancer
Stratify
depth of tumor
penetration 5-FU/leucovorin x 1
5-FU/leucovorin
+
4500 cGy
radiation
5-FU/leucovorin x 2
number involved
nodes
location of tumor observation
extent of surgery
R
A
N
D
O
M I
Z
E
Macdonald JS, et al. N Engl J Med. 2001;345(10):725-730.
Intergroup Protocol 0116Adjuvant Therapy for Gastric Cancer
Macdonald JS, et al. N Engl J Med. 2001;345:725-730.
Smalley SR, et al. J Clin Oncol. 2012; 30:2327-2333
Chemoradiotherapy
Surgery Only
50%
41%
3 years
Intergroup Protocol 0116
ECF x 3 q3/52
3-6 weeks
Resection
ECF x 3 q3/52
6-12 weeks
CSC S
Follow-up
Within 6 weeks
Resection
Cunningham D, et al. N Engl J Med. 2006;355:11-20. 503 Patients:
15% Lower Third12% GE Junction
MAGIC Trial: Schema
MAGIC: Survival
FLOT4 Study Design
FLOT x4 - RESECTION - FLOT x4
ECF/ECX x3 - RESECTION - ECF/ECX
x3
• Gastric cancer or
adenocarcinoma of
the gastro-esophageal
junction type I-III
• Medically and
technically operable
• cT2-4/cN-any/cM0 or
cT-any/cN+/cM0
R
n=716
S
T
RA
T
I
F
I
CA
T
I
O
N
FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1;
leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every
two weeks
ECF/ECX: Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1;
5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided
into two doses d1-d21), every three weeks
Stratification: ECOG (0 or 1 vs. 2), location of primary (GEJ type I vs.
type II/III vs. stomach), age (< 60 vs. 60-69 vs. ≥70 years) and nodal
status (cN+ vs. cN-).
Presented by: Salah-Eddin Al-Batran
Randomized, multicenter, investigator-initiated, phase II/III study
FLOT4: Progression-Free Survival
ECF/ECX FLOT
mPFS 18 months 30 months
[15-22] [21-41]
HR 0.75 [0.62-0.91]
p=0.004 (log rank)
2y 43% 53% 3y 37% 46% 5y 31% 41%
PFS rate* ECF/ECX FLOT
*projected PFS rates
Presented by: Salah-Eddin Al-Batran
FLOT4: Overall Survival
ECF/ECX FLOT
mOS 35 months 50 months
[27-46] [38-na]
HR 0.77 [0.63 - 0.94]
p=0.012 (log rank)
2y 59% 68% 3y 48% 57% 5y 36% 45%
OS rate* ECF/ECX FLOT
*projected OS rates
Presented by: Salah-Eddin Al-Batran
FLOT 4: Toxicity
Grade 3-4 >5% ECF/ECX (N=354) FLOT (N=354) P-value (Chi-Square)
Diarrhea 13 (4%) 34 (10%) 0.002
Vomiting 27 (8%) 7 (2%)
Localized Gastric:
Post-operative 5-FU-based chemoradiation therapy remains
one standard of care for muscle-invasive or LN positive
disease.
The peri-operative FLOT4 regimen appears to be an
improvement over MAGIC/ECF and should be considered
for patients of better performance status.
Conclusions from these Results
What are the Active Agents and
Combinations for this Disease?
Metastatic Esophagogastric Cancer
Evolution of Therapy in Advanced Esophagogastric Cancer
FAM < FAMTX
CF = ELF = FAMTX > EAP
5-FU < FAM
PELF = FAMTX < ECF
ECF > MCF
ECF = ECX = EOF = EOX
DCF > CF CF = FOLFIRIFOL = CFFOX
DC < DCF IP < FOLFIRI
Randomized Phase III
Randomized Phase II
Multi-center Phase II
FOLFOX
FOLFIRI = EOXmDCFFOL =ECFFOX
CALGB 80403 / ECOG E1206: Schema
Stratification:
ECOG 0-1 vs 2
ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 → 250mg/m2 IV, weekly
Epirubicin 50 mg/m2 IV, day 1
Cisplatin 60mg/m2 IV, day 1
Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 → 250mg/m2 IV, weekly
Cisplatin 30 mg/m2 IV, days 1 and 8
Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 → 250mg/m2 IV, weekly
Oxaliplatin 85 mg/m2 IV, day 1
Leucovorin 400 mg/m2, day 1
Fluorouracil 400 mg/m2 IV bolus, day 1
Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
Enzinger. J Clin Oncol 2016
CALGB 80403 / E1206: Survival
FOLFOX-C has similar efficacy to ECF-C in Esophageal and GEJ Cancer
Progression-Free Survival Overall Survival
0 5 10 15 20 25 30
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y O
vera
ll S
urv
ival
67 55 38 23 14 10 473 56 33 21 13 10 5
73 61 41 24 14 6 5
Number of Patients at Risk
ECF-CIC-C
FOLFOX-C
Events n/N (%)
Median months
95% CI
ECF-C 63/67 (94.0%) 11.6 8.1-13.4
IC-C 68/73 (93.2%) 8.6 6.0-12.4 FOLFOX-C 65/73 (89.0%) 11.8 8.8-13.9
Log-rank test p=0.61
0 5 10 15 20 25 30
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
Pro
gre
ss
ion
-fre
e S
urv
iva
l
67 41 17 7 5 5 3
73 35 11 5 4 1 073 47 22 8 8 3 2
Number of Patients at Risk ECF-C
IC-CFOLFOX-C
Events n/N (%)
Median months
95% CI
ECF-C 65/67 (97.0%) 7.1 4.5-8.4
IC-C 72/73 (98.6%) 4.9 3.9-6.0 FOLFOX-C 70/73 (95.9%) 6.8 5.4-8.1
Log-rank test p=0.09
Treatment modifications:
FOLFOX-C (73%) vs IC-C (85%) vs ECF-C (91%) (χ2, p=0.013).
Discontinued treatment for adverse event or treatment-related death:
FOLFOX-C (11%) vs. ECF-C (19%) vs IC-C (26%) (χ2, p=0.17).Enzinger. J Clin Oncol 2016
Time to Progression Overall Survival
Grade 3-4 Toxicity DCF CF
Neutropenia 82% 57%
Febrile Neutropenia 29% 12%
Stomatitis 21% 27%
Diarrhea 19% 8%
Vomiting 14% 17%
Van Cutsem et al.
J Clin Oncol 2006
Phase III: DCF vs CF for Esophagogastric Cancer
Shah et al. JCO 2015;33:3874-3879
Grade 3-4 Toxicity mDCF DCF
Neutropenia w GCSF 56% 45%
Febrile Neutropenia 9% 16%
Stomatitis 0 13%
Diarrhea 6% 3%
Vomiting 2% 19%
Randomized PII: Modified DCF vs. DCF for Met Gastric
Guimbaud. J Clin Oncol 2014
Phase 3: FOLFIRI vs ECX for Met Gastric/GEJ
Previously
untreated patients
with locally
advanced or
metastatic
oesophago-
gastric cancer
R
A
N
D
O
M
I
S
A
T
I
O
N
Epirubicin
Cisplatin
Fluorouracil
Epirubicin
Cisplatin
Xeloda (capecitabine)
Epirubicin
Oxaliplatin
Fluorouracil
Epirubicin
Oxaliplatin
Xeloda (capecitabine)Stratified for:
- Center (63 centers, mainly UK, 2 Aus)
- Locally advanced vs metastatic
- PS 0/1 vs 2
2 x 2 design
Cunningham D, et al. N Engl J Med. 2008;358:36-46.
REAL-2: Schema
0
20
40
60
80
100
0 1 2 3Time since randomisation (years)
Pro
bab
ilit
y of
su
rviv
al (
%)
ECF EOF ECX EOX
Arm OS (m) 1-year survival
(95% CI)
P-value HR
(95% CI)
ECF
EOF
ECX
EOX
9.9
9.3
9.9
11.2
37.7 (31.8-43.6)
40.4 (34.2-46.5)
40.8 (34.7-46.9)
46.8 (40.4-52.9)
0.612
0.389
0.020
1
0.96 (0.79-1.15)
0.92 (0.76-1.11)
0.80 (0.66-0.97)
Cunningham D, et al. N Engl J Med. 2008;358:36-46.
EOX
ECF
REAL-2: Survival (ITT)
IntelliDose chemotherapy order entry (COE) platform:Trends in metastatic gastric cancer chemotherapy treatment* (2005-2016 )
Year of initiation of first-line therapy
N=4,333
Year of initiation of second-line therapy
N=1,822
2005-09 2010-12 2013-14 2015-16 2005-09 2010-12 2013-14 2015-16
N 1,073 1,357 948 883 N 465 604 424 329
FOLFOX (%) 12.0 21.2 35.1 41.0 FOLFOX (%) 13.3 13.1 17.2 16.4
ECF/EOX (%) 13.8 23.0 11.6 10.2 ECF/EOX (%) 11.2 7.9 5.4 3.0
DCF (%) 22.9 14.3 11.8 8.4 DCF (%) 15.7 9.3 7.3 2.1
CF (%) 12.6 10.8 7.9 7.2 CF (%) 4.3 4.6 3.3 3.3
TAX (%) 4.8 4.1 3.8 6.3 TAX (%) 11.8 11.4 21.0 22.8
C+Irinotecan (%) 9.0 2.8 1.1 1.5 FOLFIRI (%) 11.2 9.1 12.0 9.7
C+TAX (%) 9.8 12.2 15.6 14.6 C+TAX (%) 7.1 19.7 7.5 7.6
FU mono (%) 9.2 7.5 8.1 6.5 FU mono (%) 9.2 112.1 13.0 22.2
Other (%) 5.9 4.1 5.0 4.3 Other (%) 14.8 11.9 13.0 11.9
FOLFOX=fluoropyrimidine (FU) + oxaliplatin ; ECF/EOX=epirubicin + platinum + FU ; DCF=docetaxel (D) + cis/carboplatin (C) + FU ;
CF=C + FU; TAX=taxane; DF = D + FU* With or without biologic agents
Abrams T et al. GI Cancers Symposium 2018
HER2-positive
advanced GC
(n = 584)
5-FU or capecitabine
+ cisplatin
(n = 290)
R
aChosen at investigator’s discretion
GEJ, gastroesophageal junction
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n = 294)⚫ Stratification factors
− Advanced vs metastatic
− GC vs GEJ
− Measurable vs non-measurable
− ECOG PS 0-1 vs 2
− Capecitabine vs 5-FU
Phase III, randomized, open-label, international, multicenter study
Bang, Y-J et al. Lancet 2010; 376:687
3807 patients screened1
810 HER2-positive (22.1%)
ToGA - Schema
(HER2 3+ or 2+/FISH+)
ToGA: Overall Survival
2.7 mo.
Is 2nd line therapy of benefit?
Metastatic Esophagogastric Cancer
R
A
N
D
O
M
I
Z
E
Docetaxel 75
mg/m2 q 3 weeks
Best supportive
care
168 patients :
Primary Endpoint:
Overall
Survival
Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.
Cougar-02: Randomized Trial of Docetaxel vs. BSC in
Relapsed Esophagogastric Adenocarcinoma
3.6 mo 5.2mo
HR: 0.67, 95% CI 0.49–0.92;
p=0.01
Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.
Cougar – 02: 2nd line Docetaxel vs. BSC: Overall Survival
Ramucirumab 8 mg/kg
q2wk
+
BSC (n = 238)
R
A
N
D
O
M
I
Z
E
Placebo q2wk
+
BSC (n = 117)
S
C
R
E
E
N
Treatment until disease progression
or intolerable
toxicity
Tumor assessment, survival, and safety follow-
up
N = 355
• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
• Gastric or GEJ adenocarcinoma
• Stratification factors: region, weight loss (≥10% vs.
Months
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28
Overa
ll S
urv
ival
0.0
0.2
0.4
0.6
0.8
1.0
Ramucirumab
Placebo
Censored
Censored
Ram 238 154 92 49 17 7 3 0 0
Plcb 117 66 34 20 7 4 2 1 0
No. at Risk
HR (95% CI) = 0.776 (0.603, 0.998)
Log rank P-value (stratified) = 0.0473
Ramucirumab Placebo
Patients / Events 238 / 179 117 / 99
Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)
6-month OS 42% 32%
12-month OS 18% 11%
REGARD: Overall Survival
Δ mOS = 1.4 months
Fuchs et al. Lancet. 2014 Jan 4;383(9911):31-9.
Treat until
disease
progression
or intolerable
toxicity
• Important inclusion criteria:- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
•Stratification factors:- Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Survival and
safety follow-
up
RAINBOW: Study Design
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
1:1
Wilke et al. Lancet 2014; 15: 1224-35
RAINBOW: Overall Survival
RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Wilke et al. Lancet 2014; 15: 1224-35
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PTX PBO + PTX
Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)
6-month OS 72% 57%
12-month OS 40% 30%
Major Response Rate 28% 16%
Duration of Response 4.4mo 2.8mo
Δ mOS = 2.3 months
Censored
No benefit for angiogenesis inhibitors in frontline:
AVAGAST: Bevacizumab AVATAR: Bevacizumab
RAINFALL: Ramucirumab ZAMEGA: Ziv-Aflibercept
ONO-4538-12 (Attraction-2): Phase 3 Study of Nivolumabvs Placebo in Patients With Refractory GC
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.
Study Design and Endpoints
Key eligibility criteria:•Age ≥20 years•Unresectable advanced or recurrent GC or GJC•Histologically confirmed adenocarcinoma•Prior treatment with ≥2 regimens and refractory to/intolerant of standard therapy•ECOG PS of 0 or 1
Nivolumab3 mg/kg IV Q2W
R
2:1
• Stratification based on:– Country (Japan vs Korea vs Taiwan)– ECOG PS (0 vs 1)– Number of organs with metastases (
ONO-4538-12 (Attraction-2): Response & Survival
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.
KEYNOTE-059: Phase 2 Study of Pembrolizumab for Advanced Gastric or GEJ Adenocarcinoma
Primary end point: ORR per RECIST v1.1 by central review
aThe first 40 patients enrolled regardless of PD-L1 expression. Enrollment after the first 40 patients will be determined based on the results of an interim analysis. b20 patients from Asian sites and 20 patients from non-Asian sites will be enrolled. Analysis cut-off date: Nov. 10, 2014.
Pembrolizumab 200 mg + Cisplatin + 5FU, all Q3W
Pembrolizumab200 mg Q3W
Pembrolizumab200 mg Q3W
COHORT 2
• PD-L1+ or PD-L1–
• No prior systemic therapy
N = 40b
COHORT 1
• PD-L1+ or PD-L1–
• ≥2 prior systemic treatments
N = 180a
COHORT 3
• PD-L1+ only• No prior systemic therapy
N = 50
Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
Cohort 1: Response by PD-L1 & MSI Expression
ResponseaPD-L1 Positive
(n = 148)
PD-L1 Negative
(n = 109)
% 95% CI % 95% CI
ORR (CR + PR) 15.5 10.1–22.4 6.4 2.6–12.8
CR 2.0 0.4–5.8 2.8 0.6–7.8
PR 13.5 8.5–20.1 3.7 1.0–9.1
DCRb 33.1 25.6–41.3 19.3 12.3–27.9
ResponseaMSI-High
(n = 7)
Not MSI-High
(n = 167)
% 95% CI % 95% CI
ORR (CR + PR) 57.1 18.4–90.1 9.0 5.1–14.4
CR 14.3 0.4–57.9 2.4 0.7–6.0
PR 42.9 9.9–81.6 6.6 3.3–11.5
DCRb 71.4 29.0–96.3 22.2 16.1–29.2Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
Cohort 1: Treatment Exposurea and Duration of Response
Median DoR
mos (95% CI)
All patients 8.4 (1.6+b to 17.3+)
PD-L1 positive 16.3 (1.6+ to 17.3+)
PD-L1 negative 6.9 (2.4 to 7.0+)
Con
firm
ed r
esp
on
der
s (n
= 3
0)
Time since first dose (months)
CR
PR
Progressive disease
Death
Ongoing pembrolizumab treatment
0 2 4 6 8 10 12 14 16 18 20 22 24
aPatients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 post-baseline assessment
were included (n = 30). Bar length indicates time to last imaging assessment. bNo progressive disease at last disease
assessment.
Data cutoff on January 16, 2017.Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
Conclusions from these Results
Metastatic Esophagogastric:
The most active single agents are the fluoropyrimidines, platinum
analogues, taxanes, and irinotecan.
1st Line: Fluoropyrimidine & platinum combos are standard.
Trastuzumab should be added for HER2/neu 3+ or FISH+ tumors.
Pts should receive at least 2-3 lines of therapy for their dz.
2nd Line: Paclitaxel + Ramucirumab is probably the best choice for
most patients. Checkpoint inhibitors should be given for MSI-H.
Checkpoint inhibitors should be offered to all PD-L1 positive pts.
References:
• Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003; 349 (23): 2241-52. PMID: 14657432
• Enzinger PC et al. CALGB 80403 (Alliance) /E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancer. J Clin Oncol. 2016 Aug 10;34(23):2736-42. PMID: 27382098
• Van Hagen P et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. PMID: 22646630
• Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet , Volume 376 , Issue 9742 , 687 – 697 PMID: 20728210
• Fuchs CS et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0013. [Epub ahead of print] PMID: 29543932
PMID:
20728210
https://www.ncbi.nlm.nih.gov/pubmed/29543932